Crystallization is conventionally referred to as a process of the formation of solid crystals precipitating from a solution or melt or rarely deposited directly from a gas. Conventionally, the crystallization process consists of two major events, namely, nucleation and crystal growth. Nucleation is the step wherein the solid molecules disperse in the solvent start to form clusters on the nanometer scale. The stable clusters are denominated “nucleate”. Whenever the clusters are not stable, they re-dissolve. In order for the clusters to become stable, they have to reach a critical size. The critical size depends on operating conditions such as temperature, supersaturation, etc. At a stage of nucleation, the atoms in the substance to be crystallized arranged in a defined manner that defines the crystal structure.
The term “crystal structure” refers to the relative arrangement of the atoms rather than the macroscopic properties of the crystal, which is in turn defined by parameters such as size and shape. The properties of the crystal are typically the result of the (internal) crystal structure.
Subsequent to the nucleation, the crystal growth occurs, which is the growth of a nucleate that succeeds in achieving the critical cluster size. The driving force of the crystallization process comprising nucleation and crystal growth is the supersaturation. The size of the crystals depends upon the conditions to either favour the nucleation or the growth of the nuclei. Once the supersaturation is exhausted, the solid liquid system reaches the equilibrium and the crystallization process is complete. The operation conditions can be modified from the equilibrium so as to supersaturate again.
Many compounds have the ability to crystallize with different crystal structures, a phenomenon called polymorphism. Each polymorph represents a different thermodynamic solid state and crystal polymorphs of the same compound exhibit different physical properties, e.g., the solution rate, shape, melting point, etc. Polymorphism is of a major importance in industrial manufacture of crystalline products.
Crystallization may be used in the industry in order to provide highly purified products, in order to obtain salts or other crystalline end products.
For a crystallization, or re-crystallization to occur from a solution, the solution must be supersaturated. This means that the solution has to contain more solute entities (molecules or ions) dissolved that it would contain under the equilibrium, i.e., the saturated solution. Supersaturated conditions can be achieved by various methods such as solution cooling, addition of secondary solvents to reduce solubility of the solute (antisolvent or drown out technique), chemical reaction or change in pH. All of these methods are employed in industrial practice. Also, solvent evaporation can be used.
FIG. 1 exhibits a saturation curve, i.e. graph, which shows the borderline between unsaturated and supersaturated solution. In practice, between the saturation curve and the supersaturation curve, a so-called meta-stable region occurs. Between the saturation curve and the supersaturation curve, a spontaneous crystallization of the solid takes place in this meta stable region. In order to enter the left-handed region, i.e., the supersaturated solution, the temperature may be rapidly decreased without changing the amount of substance per volume of solution (so-called cooling crystallization), the amount of substance per volume of solvent may be rapidly increased at a constant temperature, e.g., by vaporization (so-called vaporization crystallization), or both temperature and amount of substance per volume of solvent are rapidly changed simultaneously, i.e. the temperature is decreased, while the amount of substance per volume is increased (so-called vacuum crystallization). Once a simple saturated solution is obtained, a seed crystal is then introduced in order to induce the crystallization process.
Conventional industrial equipment for crystallization makes use of cooling crystallization, vaporization crystallization and vacuum crystallization.
One example for vaporization crystallization equipment is the so-called circulating liquid evaporator crystallizer. The circulating liquid is drawn by a screw pump down inside the tube side of the condensing stream heater. The heated liquid then flows into the vapour space where flash evaporation occurs resulting in supersaturation. The vapour leaving is condensed. The supersaturated liquid flows down the downflow tube and then up through the bed of fluidized and agitated crystals. The crystals grow in size. The leaving saturated liquid then goes back as a recycle stream to the heater where it is joined by the entering fluid. The larger crystals settle out and the slurry of crystals and mother liquid is withdrawn as a product.
An example for cooling crystallization is realized in classical tank crystallizers. Saturated solutions are allowed to cool in open tanks. After a period of time, the mother liquid is drained and the crystals are removed.
One example for a vacuum crystallizer is the so-called circulating magma vacuum crystallizer. A suspension (magma) of crystals is circulated out of the main body of the apparatus through a circulating pipe by a screw pump. The magma flows through a heater where the temperature is raised. The heated liquid then mixes with body slurry and boiling occurs at the liquid surface. This causes supersaturation in the swirling liquid near the surface, which deposits in the swirling suspended crystals until they leave again via the circulating pipe. The vapours leave through the top. A steam jet ejector provides a vacuum.
While these classical crystallization methods employ seed crystals for initiating the crystallization process, other methods have been described, wherein nucleation and crystal growth are initiated without the need for seed crystals. DE 60310923 describes the production of crystals using high power ultra sound. The method is in particular useful for the production of highly pure crystals under aseptic conditions. Highly purified products to be produced under aseptic conditions normally lack the presence of seed crystals since both solution and surfaces of the production apparatus are too clean to allow the presence of seed crystals.
Hydrates are inorganic or organic substances that contain crystal bound water. The water molecules are combined with the molecule in a definite ratio as an integral part of the crystal. The notation of hydrate compounds is “nH2O”, wherein n is the number of water molecules per molecule of salt. “n” is usually a low integer although it is possible that fractioned values exist. In a monohydrate n is 1; in a hexahydrate n is 6, etc.
The stability of hydrates is generally determined by the nature of the compounds, their temperature and the relative humidity if they are exposed to an open surrounding. Inorganic and organic compounds exist in various hydrates.
One example is sodium selenite (Na2SeO3), which exists in an unhydrated form (without crystal bound water) as a pentahydrate Na2SeO3×5H2O) as well as an octahydrate (Na2SeO3×8H2O). The crystallization of highly purified species is not possible using conventional crystallization processes, in particular when the high purity standards have to be met. Given the lability of the various hydrates, it is in particular necessary to work under precise conditions in order to obtain a homogenous composition of precisely defined crystal water content, i.e., a composition which does not contain too much bound crystal water nor suffers from loss of crystal water.
Sodium selenite pentahydrate is listed in the monographs of European pharmacopeia (Ph. Eur. 1677) and in order to fulfil the restrictive standards of the pharmacopeia, the active substance approved as a pharmaceutical has to fulfil all requirements given in the monograph.
Janitzki et al., Über die selenig säuren Salze des Natriums und des Kaliums. Zeitschrift für Anorganische und allgemeine Chemie 205 (1932):49-75 describes sodium selenic pentahydrate to be stable between −8.7° C. and 39.5° C. Below the temperature range the octahydrate exists whereas above 38.5° C., the anhydrous material is stable. Conventionally, sodium selenic pentahydrate for the pharmaceutical field was produced employing evaporation and cooling techniques.
Unfortunately, the production of highly purified sodium selenite pentahydrate meeting the standards of the pharmacopeia is incompletely described in the prior art, hardly reproducible and does not meet the GMP Guidelines for the manufacturing of Active Pharmaceutical Ingredients (API's).
Sodium selenite pentahydrate is a good example that there is a need in the field for a new manufacturing process for well-defined and highly pure crystals, preferably useful in the pharmaceutical field.